Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.

Abstract

To update and reanalyze 2 systematic reviews to examine the effects of calcium intake on cardiovascular disease (CVD) among generally healthy adults.

Data Sources:

MEDLINE; Cochrane Central Register of Controlled Trials; Scopus, including EMBASE; and previous evidence reports from English-language publications from 1966 to July 2016.

Study Selection:

Randomized trials and prospective cohort and nested case–control studies with data on dietary or supplemental intake of calcium, with or without vitamin D, and cardiovascular outcomes.

Data Extraction:

Study characteristics and results extracted by 1 reviewer were confirmed by a second reviewer. Two raters independently assessed risk of bias.

Data Synthesis:

Overall risk of bias was low for the 4 randomized trials (in 10 publications) and moderate for the 27 observational studies included. The trials did not find statistically significant differences in risk for CVD events or mortality between groups receiving supplements of calcium or calcium plus vitamin D and those receiving placebo. Cohort studies showed no consistent dose–response relationships between total, dietary, or supplemental calcium intake levels and cardiovascular mortality and highly inconsistent dose–response relationships between calcium intake and risks for total stroke or stroke mortality.

Although adequate calcium and vitamin D intake is critical for maintaining bone health, the role of calcium and vitamin D supplementation in older adults is unclear. Some systematic reviews showed that combined calcium and vitamin D supplementation reduced the risk for fractures in older adults (2, 3), whereas more recent systematic reviews reported inconsistent effects for fractures across randomized, controlled trials (4, 5). Experts have raised concerns about a potential effect of a high intake of calcium (with or without vitamin D) from foods and supplements on cardiovascular disease (CVD) outcomes (6–8). A meta-analysis of both study- and patient-level data from randomized trials showed that calcium with or without vitamin D supplementation increased the risk for myocardial infarction (pooled relative risk, 1.24 [95% CI, 1.07 to 1.45]) and stroke (pooled relative risk, 1.15 [CI, 1.00 to 1.32]) (9, 10). However, a more recent meta-analysis showed that calcium with or without vitamin D supplementation had no statistically significant effects on coronary heart disease events (pooled relative risk, 1.02 [CI, 0.96 to 1.09]) or mortality (pooled relative risk, 1.04 [CI, 0.88 to 1.21]) (11). Many researchers have questioned the strength of the body of evidence linking supplemental calcium intake with CVD risk, noting that cardiovascular outcomes have not been the primary end point of any trial investigating calcium or calcium and vitamin D supplementation to date (12, 13).

To inform a joint position statement from the National Osteoporosis Foundation (NOF) and American Society for Preventive Cardiology, NOF commissioned a focused update and reanalysis of 2 broader evidence reports examining the effects of calcium and vitamin D on a wide range of clinical and intermediate outcomes (5, 14). This update addresses the effects of calcium intake (from dietary or supplemental sources), alone or in combination with vitamin D, on CVD risk in generally healthy adults.

Methods

This systematic review implemented the same methodology as the 2009 evidence report examining the effects of calcium and vitamin D (alone or in combination) on 17 health outcomes across all life stages that was produced to inform the Institute of Medicine committee charged with updating the dietary reference intake values for calcium and vitamin D (14). In 2014, the Agency for Healthcare Research and Quality commissioned an update of the 2009 evidence report focusing on studies of vitamin D alone or in combination with calcium (5). The effects of calcium intake (from foods or supplements) alone on CVD were not updated in the 2014 evidence report. Methodological details for the reviews were described in a protocol (15).

Data Sources and Searches

MEDLINE, the Cochrane Central Register of Controlled Trials, and Scopus (including EMBASE) were searched from 2009 to July 2016 for prospective cohort or nested case–control (or case–cohort) studies reporting an association between calcium intake (dietary or supplemental) and risk for incident CVD (cardiac, cerebrovascular, or peripheral vascular events and new hypertension), and for randomized, controlled trials on the effect of increasing calcium intake (by food or supplements) on the same outcomes. Analyses of combinations of calcium and micronutrients other than vitamin D that could not isolate the independent effects of calcium with or without vitamin D were not included. Studies or analyses that did not quantify the amount of calcium in the interventions or exposures also were excluded. The literature search strategy was adapted from the 2009 evidence report (14) but focused on calcium exposures and CVD outcomes. Unpublished data were not sought.

Study Selection

Two reviewers performed abstract and full-text screening to identify peer-reviewed, English-language studies of generally healthy adults in which no more than 20% of participants had known CVD. Studies involving participants with hypertension or elderly populations (>60 years of age) were included, whereas those restricted to pregnant women, persons with diabetes, or those receiving dialysis were excluded. Reference lists of relevant systematic reviews were cross-checked with lists of included studies to ensure that no relevant studies were missed. All cardiovascular event or mortality outcomes (defined by the original authors) were included.

Data Extraction and Risk-of-Bias (Quality) Assessment

All extracted data in the 2009 and 2014 evidence reports (5, 14) are accessible to the public on PubMed and PubMed Health. Relevant data in the 2 evidence reports were extracted from their evidence tables (Appendix C of the evidence reports) and are included in this update. Data from studies published after the 2 evidence reports were extracted by 1 reviewer and confirmed by at least 1 other using the same data extraction form. The risk of bias in randomized, controlled trials and that of observational studies was assessed separately, with the same assessment tools used in the 2009 and 2014 evidence reports (15). However, to be consistent with the current methodology recommended in the Cochrane Handbook for Systematic Reviews of Interventions, we did not assign an overall quality grade for each study in this update (16). Two reviewers did the risk-of-bias assessments independently; disagreements were discussed until consensus was reached.

Data Synthesis

We synthesized trials and cohort studies separately but based our conclusions on the total body of evidence. We did not perform a meta-analysis of trial data, because trials reported outcomes with heterogeneous definitions. For cohort studies, we charted dose–response curves by using adjusted results and did dose–response metaregressions if 4 or more studies reported analyses of similar exposure–outcome relationships. If more than 1 analysis model was reported in a study, we focused on the model that adjusted for the most potential confounders. Many cohort studies had several analyses reporting different calcium exposures or cardiovascular outcomes of interest. We planned our dose–response metaregressions carefully to ensure that study populations did not overlap in each analysis.

We performed linear and nonlinear dose–response metaregressions to examine the associations between calcium intake levels and the risk for CVD by using a 2-stage hierarchical regression model, implemented in the dosresmeta R package (17, 18). The method, first formalized by Greenland and Longnecker (19), uses estimates of the covariance matrix to account for the within-study correlations across dose levels and incorporates them into the estimation of the linear trend by using generalized least-squares regression. In addition, we applied a method developed by Hamling and colleagues (20) that allowed reconstruction of a table of cell counts (“effective counts”) from reported adjusted risk estimates and CIs. We used this method to facilitate dose–response metaregressions and recalculate risk estimates comparing calcium dose categories greater than 1000 mg/d with those less than 1000 mg/d, the recommended dietary allowance for healthy adults (1). See the Appendix for details of these procedures.

Analyses were conducted by using SAS, version 9.3 (SAS Institute), and R, version 3.2.5 (R Foundation for Statistical Computing). All P values were 2-tailed, and a P value less than 0.05 was considered statistically significant.

Role of the Funding Source

This research was supported by an unrestricted educational grant from the NOF through Pfizer Consumer Healthcare. The authors were blind to the corporate funder until the final manuscript was submitted to the NOF. The funder reviewed the evidence synthesis for drafting the position statement but had no role in study selection, quality assessment, data analysis, or writing the manuscript.

Appendix Table 3. Results From the 10 Randomized, Controlled Trial Publications Examining the Effects of Calcium With or Without Vitamin D Supplementation on CVD

Appendix Table 3. Results From the 10 Randomized, Controlled Trial Publications Examining the Effects of Calcium With or Without Vitamin D Supplementation on CVD

Several publications analyzed data from the WHI trial (10, 22–26, 29), which randomly assigned 36 282 postmenopausal U.S. women (aged 50 to 79 years) to receive either 1000 mg of calcium plus 400 IU of vitamin D3 daily or placebo. Six reports examined CVD outcomes at the end of 7 years of supplementation (10, 23–26, 29), and 1 report (22) included CVD outcomes 5 and 12 years after intervention. Outcomes reported in these articles included myocardial infarction, coronary heart disease events or mortality, total heart disease, total CVD, CVD mortality, cerebrovascular death, coronary artery bypass grafting or percutaneous coronary intervention, confirmed angina, hospitalized heart failure, stroke (ischemic, hemorrhagic, or other), transient ischemic attack, and heart failure. Several publications reported post hoc subgroup analyses comparing effects in women using calcium supplements during the trial with those in women not using these supplements, across various age groups or between groups with low and high baseline CVD risk. Only 2 subgroup analyses revealed statistically significant differences between groups. One showed that use of personal calcium supplements altered the effect of calcium and vitamin D on CVD (10). In postmenopausal women receiving calcium supplements, the hazard ratios with calcium and vitamin D were 1.13 to 1.22 for CVD end points. In contrast, among those not taking supplements, the hazard ratios were 0.83 to 1.08. The other subgroup analysis found a lower risk for heart failure with calcium and vitamin D supplementation in postmenopausal women without preexisting heart failure precursors at baseline (hazard ratio, 0.63 [CI, 0.46 to 0.87]) but no statistically significant effect of supplementation in those with heart failure precursors and conditions (hazard ratio, 1.06 [CI, 0.90 to 1.24]) (Appendix Table 3) (23). The RECORD trial examined the effects of 3 years of daily supplementation with 1000 mg of calcium, 800 IU of vitamin D3, or both on CVD deaths and cerebrovascular disease deaths among 5292 patients (85% female and older than 70 years) recruited from fracture clinics or orthopedic wards in England and Scotland (21). Calcium plus vitamin D supplementation had no statistically significant effect on all vascular disease deaths compared with placebo (risk ratio, 0.99 [CI, 0.82 to 1.20]).

Effects of Calcium Supplementation

Three trials examined the effects of supplementation with calcium alone (doses ranging from 1000 to 1200 mg/d) on various CVD outcomes (21, 27, 28). CAIFOS (Calcium Intake Fracture Outcome Study) from Western Australia examined the effects of 1200 mg of calcium carbonate daily for 5 years on risks for atherosclerotic vascular disease among 1460 elderly women (older than 70 years) recruited from the general population (27). The Auckland calcium study randomly assigned 1471 postmenopausal women (older than 55 years) to receive 5 years of daily supplementation with 1000 mg of calcium citrate or placebo and examined the outcomes of myocardial infarction and stroke 5 years after intervention (28). The RECORD trial (described earlier) reported the effects of calcium supplementation alone on cardiovascular and cerebrovascular deaths (21). None of the studies found a statistically significant effect of calcium supplementation on CVD outcomes (hazard ratios, 0.82 to 1.43) (Appendix Table 3).

Prospective Cohort and Nested Case–Control Studies

Twenty-six cohort studies and 1 nested case–control study examined the relationships between calcium intake levels (from foods or supplements) and the risks for CVD outcomes among adults living in the United States (29, 31, 32, 34, 36, 42, 47, 48, 51, 52, 54), Europe (37–41, 43, 46, 55), Asia (30, 35, 44, 45, 49, 50), and Australia (33, 53). Of these investigations, 3 were conducted in the urses' Health Study (36, 42, 52) and 3 in the Health Professionals Follow-up Study (31, 32, 51) cohorts and 2 were done in the Swedish Mammography Cohort (41, 55). No overlaps occurred among other study populations. No study evaluated the interaction between calcium and vitamin D intake in relation to CVD outcomes. The baseline ages ranged from 17 to 99 years, and 2 cohorts exclusively enrolled individual persons older than 60 years (35, 40). Cohort sample sizes ranged from 755 to 388 229, and follow-up ranged from 8 to 30 years (Appendix Table 4). Calcium intake was assessed by food-frequency questionnaires in all but 2 cohorts (40, 47). Most studies reported CVD mortality outcomes, assessed by death certificates, International Classification of Diseases codes, medical records, or self-report.

A wide variety of CVD outcomes was reported across the 27 studies, some of which analyzed different sources of calcium separately (Supplement 1). The risk of bias of individual studies ranged from low to moderate (Appendix Table 5). All studies reported at least 1 analysis of association between calcium intake levels and CVD mortality or stroke.

Appendix Figure 2.

Risk-of-bias assessment of prospective cohort or nested case–control studies examining the associations between calcium intake and risk for cardiovascular disease.

A. Six studies estimated the associations between total calcium intake levels and risks for cardiovascular or ischemic heart disease death. B. Twelve studies estimated the associations between dietary calcium intake levels and risks for cardiovascular or ischemic heart disease death. C. Five prospective cohort studies estimated the associations between supplemental calcium intake levels and risks for cardiovascular or ischemic heart disease death. D. Five studies estimated the associations between total or dietary calcium intake levels and risks for stroke death. E. Ten studies estimated the associations between total or dietary calcium intake levels and risks for total stroke.

Of the 15 studies, 12 reported data that allowed reanalysis using the effective counts to estimate the risk for CVD mortality, comparing calcium intake levels above with those below 1000 mg/d (reference group) (Figure 2). Three studies not included in the reanalysis were done in Asian countries (35, 44, 49); the highest intake levels in these cohorts were less than 1000 mg/d. Overall, the studies showed inconsistent results. Although most results did not reach statistical significance, 1 study (48) showed that dietary calcium intake levels greater than 1000 mg/d (reported mean calcium intake levels in quintile 5 was 1247 mg/d for men and 1101 mg/d for women) were associated with a higher risk for CVD mortality (adjusted hazard ratio, 1.06 [CI, 1.00 to 1.14] for women; adjusted hazard ratio, 1.10 [CI, 1.04 to 1.16] for men). This study also found that supplemental calcium intake (≥1000 mg/d) was associated with an elevated risk for CVD mortality compared with no supplemental intake (adjusted relative risk, 1.20 [CI, 1.05 to 1.36]) and that total calcium intake had a U-shaped association with total CVD mortality in men but not in women. The increased CVD mortality in men was observed at calcium intakes of 1500 mg/d and greater (48). Another study (54) showed that supplemental calcium intake of more than 1000 mg/d was associated with an increase in CVD mortality in men (adjusted relative risk, 1.24 [CI, 1.00 to 1.53]) but a decreased risk in women (adjusted relative risk, 0.92 [CI, 0.82 to 1.03]). In contrast, the Nurses' Health Study I found lower risks for CVD events or mortality among women who took more than 1000 mg of calcium supplements daily compared with those who did not take calcium supplements (adjusted relative risk, 0.82 [CI, 0.74 to 0.92]) (42).

Figure 2.

Reanalysis of 12 cohort studies to examine the risks for CVD, cardiac, or IHD mortality, comparing calcium intake levels 1000 mg/d or greater with those less than 1000 mg/d.

Relationships Between Calcium Intake Levels and Risks for Stroke

Twenty cohort studies assessed the association between calcium intake and stroke risk (29, 30, 32, 36, 39–41, 43–45, 47–55). Individual study results, shown in Figure 3, display analyses examining the associations between dietary or total calcium intake levels and the risks for total stroke (top) and stroke mortality (bottom). Total calcium intake levels ranged from 200 to 2400 mg/d, and very few data points extended beyond 1600 mg/d. The dose–response relationships between calcium intake levels and risks for total stroke or stroke mortality were highly inconsistent, with some studies showing opposite trends for total stroke risk. The inconsistencies could not be explained by the sex of the study populations. Risk of bias of these studies was moderate, primarily because they did not justify the final statistical models, designate which outcomes were primary, or report dietary assessment methods completely (Appendix Figure 2, D and E). Dose–response metaregression analyses did not find statistically significant linear or nonlinear relationships between levels of dietary or total calcium intake and the risk for total stroke (n = 8) or stroke mortality (n = 5) (Table).

Figure 3.

Results of 15 cohort studies examining the relationships between dietary or total calcium intake and the risks for total stroke (10 studies [top]) and stroke mortality (5 studies [bottom]).

Nine studies contributed data to the reanalysis by using the effective counts to estimate the risks for stroke mortality (3 studies) or total stroke (6 studies), comparing calcium intake levels above with those below 1000 mg/d (reference group). Although the results were inconsistent (Figure 4), 2 studies showed that a dietary calcium intake level greater than 1000 mg/d was associated with an increase in total stroke risk in men (adjusted relative risk, 1.09 [CI, 0.99 to 1.21]) (38) and women (adjusted relative risk, 1.13 [CI, 1.02 to 1.26]) (55).

Figure 4.

Reanalysis of 10 cohort studies to examine the risks for total stroke or stroke mortality, comparing calcium intake levels 1000 mg/d or greater with those less than 1000 mg/d.

HR = hazard ratio; RR = relative risk.

Data from 5 studies were not sufficient for plotting the dose–response relationships between calcium intake level and risk for stroke (29, 30, 40, 50, 54). Two of these studies reported only analyses of the association between supplemental calcium intake and the risk for stroke (29) or stroke mortality (54) compared with no calcium supplement intake. Neither study (the overall risk of bias was low) found statistically significant associations in men or women (adjusted relative risk, 0.80 to 1.03). None of the other 3 cohort studies (2 in Asia [30, 50] and 1 in Finland [40]) showed statistically significant associations between dietary calcium intake levels and the risks for stroke events or mortality in men or women (30, 40, 50). However, these studies had small sample sizes (755 to 1772) and the overall risk of bias was moderate, primarily because of incomplete data reporting regarding calcium intake levels, dietary assessment methods, and inadequate justification of final statistical models.

Discussion

On the basis of our assessments of internal validity, precision of risk estimates, and consistency of results from randomized trials and prospective cohort studies, we conclude that calcium intake (from either food or supplement sources) at levels within the recommended tolerable upper intake range (2000 to 2500 mg/d) are not associated with CVD risks in generally healthy adults. Although a few trials and cohort studies reported increased risks with higher calcium intake, risk estimates in most of those studies were small (±10% relative risk) and not considered clinically important, even if they were statistically significant.

The mechanisms by which high calcium intake might alter the risk for CVD or stroke among generally healthy adults are unclear. Very high calcium intake is difficult if not impossible to achieve by dietary sources alone. Therefore, the concerns regarding potential adverse cardiovascular risks are related to the use of calcium supplements, which has been associated with increased risk for kidney stones in postmenopausal women (56). Vascular calcification is 1 proposed mechanism for CVD events observed in trials of calcium supplements (9), but available data about calcification of vascular tissues associated with calcium supplementation are derived from persons with impaired renal function (57–59), not from the general population.

Our updated literature search identified several systematic reviews on the same topic, but none synthesized both trials and observational studies. Our findings are consistent with a recent meta-analysis of trials (11) and a meta-analysis of prospective cohort and nested case–control studies (60). However, they are inconsistent with those of several earlier meta-analyses of trials (9, 10) and cohort studies (61–63). Differences in the data synthesis methods may account for the apparent discordant results and conclusions. Earlier meta-analyses of trials did not appraise the risk of bias; some combined trials of calcium supplements used alone with those of calcium plus vitamin D supplements. All 3 earlier meta-analyses of cohort studies (61–63) reported a nonlinear dose–response relationship between calcium intake levels and stroke risks. The dose–response metaregression methods were unclear in 2 of the meta-analyses (62, 63), and results likely were incorrect because of limitations of the statistical package (glst command) for dose–response meta-analysis implemented in Stata (64). As Liu and colleagues (18) pointed out, glst does not provide solutions for pooling studies with different reference exposure doses, which is the case in all the dose–response meta-analyses of calcium intake and cardiovascular risk. Three meta-analyses of observational studies (60, 62, 63) also included “high-versus-low” or extreme-quantile meta-analyses, which produced uninterpretable pooled results, because the ranges of highest and lowest quantile categories of calcium intake varied substantially across studies. An empirical evaluation of meta-analytic approaches for nutrient and health outcome dose–response data discouraged those that use only data from extreme exposure categories, because the results typically are biased away from the null (65).

Our systematic review and meta-analyses had several limitations. We included only English-language publications; thus, language and publication bias cannot be ruled out. To date, data beyond the tolerable upper intake levels are lacking; thus, the CVD risks at very high calcium intake levels are uncertain. Our metaregressions of cohort studies had moderate risk of bias, potential residual confounding, ecological bias, and imprecise measurement of calcium exposures limited interpretations of data. Ascertainment of total calcium intake levels from foods and supplements was not well-estimated in trials because of adherence issues and was limited by the use of food-frequency questionnaires for assessing dietary exposures in observational studies. Lastly, because different cohort studies adjusted for different sets of confounders, using the risk estimates that adjusted for the most factors in the meta-analyses assumed that the different adjustments across studies would not affect the meta-analytic results—an assumption that we cannot verify without conducting simulation studies.

We believe a trial with sufficient statistical power to detect small differences in adverse cardiovascular outcomes is unlikely to be done. Our search on ClinicalTrials.gov (9 August 2016) identified no ongoing trials designed specifically to address this research question. We recommend future prospective population-based cohort studies that assess total, dietary, and supplemental calcium intake by using validated dietary assessment methodology; ascertain chronic disease outcomes by using standardized outcome measures; and use prospectively developed study protocols, power calculations, and analysis plans.

Systematic review and meta-analysis play an important role in evidence-based medicine. Apparently conflicting conclusions across several meta-analyses of the same topic may cause uncertainty in the health care community and confusion among the general public. To increase transparency, reduce research waste, minimize potential biases, and facilitate updating evidence-based information and its translation to practice or policy, we recommend that all data from systematic reviews and meta-analyses be made publicly available. Our systematic review, which synthesizes data from trials and cohort studies, has implications for a new evidence-based approach (66, 67) to establish dietary reference intake values that include chronic disease and long-term outcomes, for which direct evidence from randomized trials often is lacking. In the absence of direct evidence from trials, synthesis of large population-based cohort studies may improve the strength of evidence and provide complementary data for clinical or policy decision making.

Appendix: Technical Details

Dose–Response Metaregressions

Liu and colleagues (18) described how to use a 2-stage hierarchical metaregression model to estimate the summarized linear and nonlinear dose–response relationship. The model has been implemented in the dosresmeta R package (17). The aim of the first-stage analysis is to estimate for each study the (same) dose–response association between the adjusted log-relative risks and exposure levels, as described previously by Greenland and Longnecker (19). Their approach is based on constructing an approximate covariance estimate for the adjusted log-odds, -rate, or -risk ratios from a fitted table that conforms to the adjusted log-risk estimates and matches the crude 2 × 2 table margins. In the present analysis, an alternative approach was used. The method by Hamling and colleagues (20) was followed to get estimated cell counts, then the approach of Greenland and Longnecker was used to obtain covariance estimates and the weighted least-squares estimates. In the second-stage analysis, the study-specific estimates are combined by using the extension of the generalized least-squares method with restricted maximum likelihood estimation to fit the dose–response curves, as described by Berkey and colleagues (68).

To estimate study-specific linear trends, several approximations were made: The reported mean or the midpoint of calcium intake in each category was assigned to the corresponding relative risk. For the open categories, a mean of calcium intake was imputed that was 20% lower for the lowest category threshold or 20% higher for the highest category threshold. If the distributions of person-years or noncases were not provided but analyzed based on quantiles, they were divided equally across the quantiles. For studies that did not use the lowest category of calcium intake as the reference, the method by Hamling and colleagues (20) was used to estimate new relative risks and 95% CIs, setting the lowest category as the new reference. The Hamling group's method is described later in more detail.

Liu and colleagues (18) further described in detail how to construct the design matrix. As the dose-specific relative risks are estimated as contrasts to their reference exposure, the design matrices must be constructed similarly. In the dosresmeta function, this process is done internally by the default option center = TRUE. The argument is particularly important if the reference exposure levels vary across studies or for nonzero reference exposures. In addition, the dose–response model typically does not include the intercept, because the log-relative risk is 0 by definition for the referent value. Nonlinearity was investigated by adopting quadratic models. Statistical heterogeneity was tested using the Cochran Q statistic (considered significant if P < 0.10), and the extent of heterogeneity was quantified with the I2 index.

The R codes used to perform linear and nonlinear dose–response metaregressions are described in Appendix Table 6. The same models are used to analyze the dose–response relationships between calcium intake levels and risks for CVD mortality or for stroke events or mortality. Analytic datasets for the dose–response metaregressions in Table 1 are in Supplements 2, 3, 4, and 5. Two “dose” variables for the mean or the midpoint of calcium intake in each category are provided in the Supplements. The variable “dose2” is for sensitivity analysis.

Sensitivity analysis was performed to test the robustness of our dose–response metaregressions by changing the imputed mean of calcium intake for the open categories from 20% to 30% lower or higher for the lowest or highest category, respectively. The results shown in Table 1 were not changed.

Reanalysis Using the Effective Counts

Hamling and colleagues (20) described a method to estimate cell counts—namely the effective counts—of the 2 × 2 table adjusted for confounding, then to estimate the asymptotic correlation between the adjusted log-risk estimates for each exposure level relative to the referent level, from which we can obtain the estimated covariance matrix for these study-specific estimates. The Hamling group's method has been implemented in SAS (available at www.pnlee.co.uk/Software.htm [accessed on 6 September 2016]). These calculations were done study by study, and the effective counts are recorded in Supplement 1.

Importantly, effective counts are assumed to be consistent with the risk estimate, 95% CI, and control rates observed in the individual studies, but the data generated are neither synonymous with nor equivalent to the actual data. These estimates are simply devices used to estimate the underlying, unknown, variance–covariance matrix, which improves model fit and provides better estimates for the SEs and CIs. The numbers themselves have little or no substantive meaning.

For the reanalysis to obtain the risk estimate comparing calcium intake levels above with levels below the recommended daily allowance, we regrouped the exposure categories on the basis of the mean dose value (1000 mg/d or greater vs. less than 1000 mg/d) and calculated adjusted relative risk and its CI by using a 2 × 2 table of the effective counts of events and people at risk in each study. The contrast function also is available in the SAS codes.

Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg).

Appendix Figure 2.

Risk-of-bias assessment of prospective cohort or nested case–control studies examining the associations between calcium intake and risk for cardiovascular disease.

A. Six studies estimated the associations between total calcium intake levels and risks for cardiovascular or ischemic heart disease death. B. Twelve studies estimated the associations between dietary calcium intake levels and risks for cardiovascular or ischemic heart disease death. C. Five prospective cohort studies estimated the associations between supplemental calcium intake levels and risks for cardiovascular or ischemic heart disease death. D. Five studies estimated the associations between total or dietary calcium intake levels and risks for stroke death. E. Ten studies estimated the associations between total or dietary calcium intake levels and risks for total stroke.

Figure 2.

Reanalysis of 12 cohort studies to examine the risks for CVD, cardiac, or IHD mortality, comparing calcium intake levels 1000 mg/d or greater with those less than 1000 mg/d.

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Chung and colleagues conducted a robust meta-analysis and found no association between calcium intake and cardiovascular risk. As the authors pointed out, the strength of the evidence linking calcium supplementation with cardiovascular endpoints is weak, and a plausible biological mechanism has not been identified.

However, we disagree with the authors that data on the calcification of vascular tissues associated with calcium supplementation for the general population does not exist. We assessed the association between calcium intake and the coronary artery calcification Agatston score, evaluated from CTs, in 1200 women and men the community-based Framingham Heart Study (Am J Clin Nutr 2012;96:1274–80). We found no association between increasing Agatston scores and calcium intake from supplements and/or diet. Our prospective study, conducted in a large, community-based population of women and men, used state-of-the-art CT measures of coronary artery calcification and was able to account for important potential confounders including vitamin D intake, prevalent coronary artery disease, and kidney function.

Thus, our study, based on population data, supports the findings of Chung and co-authors, and concludes that calcium supplementation within recommended intake levels does not increase cardiovascular risk.

Aisawan Petchlorlian

KCMH

November 5, 2016

A mistake in text about interaction of personal Ca supplement in women?

In the section of results from RCT "Effects of Calcium Plus Vitamin D Supplementation", second paragraph, the author stated that"Only 2 subgroup analyses revealed statistically significant differences between groups. One showed that use of personal calcium supplementsaltered the effect of calcium and vitamin D on CVD (10). In postmenopausal women receiving calcium supplements, the hazard ratios with calcium and vitamin D were 1.13 to 1.22 for CVD end points. In contrast, among those not taking supplements, the hazard ratios were 0.83 to 1.08.".

This indicates an increase risk of intervention in women currently taking personal Ca supplement.

However in the original article of ref10, as well as in Appendix Table 3, the interaction is the other way around." In women not taking personal calcium supplements, the hazard ratios with calcium and vitamin D were 1.16 (P=0.04) for the composite end point of clinical myocardial infarction or coronary revascularisation, 1.16 (P=0.05) for clinical myocardial infarction or stroke, 1.22 (P=0.05) for myocardial infarction, and 1.13–1.20 for the other cardiovascular end points. By contrast, in women taking personal calcium supplements, the hazard ratios for these end points with calcium and vitamin D were 0.83–1.08."

Just read the last sentence I quoted from both article and see the difference.

Ian R Reid1, Alison Avenell2, Andrew Grey1, Mark J Bolland1

1. Department of Medicine Faculty of Medical and Health Sciences University of Auckland Auckland, New Zealand. 2. Health Services Research Unit University of Aberdeen Aberdeen AB25 2ZD, Scotland

November 21, 2016

Calcium and Cardiovascular Disease

In their review of calcium intake and cardiovascular disease, Chung et al did not carry out a meta-analysis of the randomized controlled trials, as their title suggested.1 They identified only 2 trials reporting the effects of calcium plus vitamin D on cardiovascular events, and 3 trials of calcium alone, whereas we have reported data on myocardial infarction or stroke from 13 studies of calcium with or without vitamin D (4 trials calcium plus vitamin D, 11 trials calcium monotherapy).2 For 6 trials we used individual patient data. As in the Chung report, cardiovascular event rates were not significantly increased in individual trials in our review, but they were when meta-analyzed (relative risk of myocardial infarction or stroke from calcium with or without vitamin D in 9 trials RR 1.15 95%CI 1.03 to 1.27).2 Another meta-analysis of calcium monotherapy (5 trials, 6,333 participants) reported a RR of 1.37 (0.98-1.92) for myocardial infarction.3 Chung provides no comment on why their findings differ from those published previously.

Surprisingly, Chung et al do not use the data from the end of each randomized trial, instead substituting data from trial extensions in which participants did not necessarily take trial medications and may have crossed-over to other treatments. On-study analyses are particularly important for examining adverse effects.

Having overlooked a considerable body of randomized research, the Chung report relies heavily on extensive analyses of observational studies which are confounded by the consistent observation that higher calcium intakes are associated with indicators of better health. In the setting of a large body of randomized trial evidence (13 trials, 29 277 participants with 1393 incident myocardial infarctions or strokes, and 1857 deaths),2 resorting to lower levels of evidence such as observational studies is neither necessary nor appropriate.

The authors suggest that a small increase in adverse events, even if statistically significant, is unlikely to be clinically significant. This is unacceptable for an intervention such as calcium supplements, taken by 30-50% of older people in some Western countries, for which risk must be balanced against the evidence from high quality trials that they do not reduce fracture risk in community-dwelling people.4 In such a setting, a probable risk of any magnitude is unacceptable.

Children's Hospital at Westmead, University of Western Australia School of Medicine and Pharmacology

November 30, 2016

Response

We read the recent meta-analysis by Chung et al (1) and National Osteoporosis Foundation and American Society for Preventative Cardiology guidelines (2) with interest and agree that there is only moderate quality evidence that calcium supplements with or without vitamin D do not effect cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults exists. It is important to note that this recommendation acknowledges that a future high-quality study or several studies with limitations are likely to impact our confidence in the estimates based on the current evidence. Given the widespread use of these supplements and the clinical uncertainty, further high-quality studies are warranted.

Of interest is the recent publication by Baron and colleagues (3) reporting the effects of 3 to 5 years of daily calcium supplements in a partial 2×2 randomized factorial trial with either; none, 1200 mg day of calcium or 1000IU of vitamin D3 or both on the risk of recurrent colorectal adenomas. In addition to the primary outcome, major adverse events adjudicated by two physicians blinded to treatment were also reported. In the no calcium group (none or vitamin D) there were 9 participants with one or more myocardial infarctions out of 835 participants (1.1%) compared to 2 participants with one or more myocardial infarctions out of 840 participants (0.2%) in the calcium supplemented group, P=0.03. These conflicting findings once again highlight the problems associated with interpreting post hoc findings from trials underpowered to determine true effects.

The editorial (4) on calcium and cardiovascular disease on what clinicians and patients need to know provides helpful advice to a confused and confusing area of clinical practice that only a few years ago was considered to be resolved after 100 years of careful research. There are however some additional insights relevant to the debate. Using mean values of calcium intake and vitamin D status, commonly reported in RCT’s, ignores the fact that unlike pharmaceuticals, the control group is exposed to some level of dietary calcium and vitamin D. So the real question being examined is what are the health benefits or risks of increasing calcium intake and vitamin D status rather than a simple yes/no exposure. However in this regard the use of meta-regression to consider the effect of high calcium intake is reassuring in that no evidence of increased risk was identified.

Calcium supplements with or without vitamin D continue to be strongly supported by expert groups for the prevention of age-related bone loss, particularly in elderly women where recommended dietary intakes often cannot be reached from food sources alone (5). These recommendations remain despite claims by the Auckland group that such expert groups are controlled by pharmaceutical companies and financial self-interest (6). Contrary to this viewpoint, it is more likely the claims of adverse effects have not been taken up by professional bodies due to the inconsistent evidence for harm as well as the approach chosen by this group including; cherry picking certain classes of adverse event (7), inconsistent validation of endpoints (8), and post hoc splitting of clinical trial data that fundamentally undermines the role of randomization (9) leading to uncertainty over whether the reported findings are real or due to chance or bias. Perhaps these latest data will allow a more rational and less emotive evidence-based view of an important public health initiative.

A blunt study design within a research field with at most modestly strong associations and a probable U-shaped biological relationship will result in null findings. This comes as no surprise. Presently many have the view that the most robust observational evidence is derived from meta-analysis of prospective studies but the results is naturally dependent on the researchers’ ability to uncover strengths and shortcomings of the individual included studies. There is a danger that meta-analyses produce very precise but equally spurious results. More is gained by carefully examining possible sources of heterogeneity between the results from observational studies (1). Mixing studies with poor and good study designs will dilute associations substantially and a true 30- to 50-fold higher risk can be reduced to a combined weak association (2).

As with any exposure assessment, self-reported recall of what you have eaten will lead to misclassification of the true dietary exposure. Repeated measurements of long term dietary intake reduce measurement error and offer opportunities to investigate changes in intake over time. Regression calibration, by use of data from a validation study, is another way to further improve accuracy of the exposure. Moreover, some studies have complete outcome identification during follow-up. Mixing studies (3) of different quality will result in diluted associations.

Since individual data was not used in their meta-analysis, Chung et al (3) instead tried to circumvent this shortcoming by a meta-regression analytical approach. However, the main dose-response meta-regression compared calcium dose categories greater than 1000 mg/day with those less than 1000 mg/day. The result of such a comparison is likely to be null given the normal distribution of calcium intake in most Western populations. A more fruitful analysis, if there is a wish to detect an excess risk with high or low calcium intakes, is to examine the risk in lowest or highest category of intake compared with the risk in a category consisting of a modest/normal intake. The result of analysis of a quadratic term by meta-regression modeling is reliant on whether the nadir in risk appears at the same calcium exposure level in different populations The calcium need, however, differ by ethnicity and by type of dietary pattern (4). A uniform risk curve with calcium intake in different populations is thus probably not the case. Indeed, differences in the position of the nadir can be readily observed in Figure 1 and Figure 3 (3).

There are several additional indications that Chung et al did not perform an in depth analysis of the individual strengths and shortcomings of the included studies. One example is that body mass index is claimed to be not reported in references 41, 47 and 55 despite the fact that body mass index is presented by exposure category in all these studies, an approach recommended by the STROBE guideline for observational studies. Another example is the statement by that no individual study investigated the interaction between calcium and vitamin D intake in relation to CVD outcomes. This is not a correct description (5).

Finally and importantly, Chung did not consider or discuss dietary calcium source in their analysis of observational studies. Type of dietary calcium source might have a larger impact on health than the amount of calcium ingested. Fermented and non-fermented dairy products, both rich calcium sources, can affect health in different directions.